The G-protein-coupled receptor GPR40 functions as a receptor for long-chain free fatty acids (FFAs) in the body. As such is implicated in a large number of metabolic conditions in the body. For example it has been alleged that a GPR40 agonist promotes insulin secretion whilst a GPR40 antagonist inhibits insulin secretion and so depending upon the circumstances the agonist and the antagonist may be useful as therapeutic agents for a number of insulin related conditions such as type 2 diabetes, obesity, impaired glucose tolerance, insulin resistance, neurodegenerative diseases and the like.
Diabetes is typically a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces to regulate blood glucose levels. Hyperglycaemia, or raised blood sugar, is a common outcome of uncontrolled diabetes and over time leads to adverse physiological changes to those suffering from the disease, especially to the nervous system and the cardiovascular system.
The World Health Organisation (WHO) estimates that more than 220 million people worldwide suffer from diabetes. In 2005, an estimated 1.1 million people died from diabetes (although the actual number is likely to be much larger as this figure does not include people who have died from diabetic complications such as heart disease or kidney failure). Of all diabetes deaths, almost 80% occur in low- and middle-income countries, almost 50% in people under the age of 70 years and approximately 55% in women. The WHO further predicts that diabetes deaths will have doubled between 2005 and 2030 unless urgent preventive steps are taken to curb or reverse this epidemic. Whilst at least a part of the diabetic epidemic can be attributed to genetic factors, the primary driver is the rapid epidemiological transition associated with changes in dietary patterns and decreased physical activity, as evident from the higher prevalence of diabetes in the urban population.
Whilst a healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of the disease, there are currently no effective therapeutic strategies for the prophylaxis or treatment of diabetes.
The pathogenesis of type 2 diabetes is characterized by beta cell dysfunction and progressive insulin resistance with compensatory hyperinsulinemia, followed by declining insulin secretion and increasing hyperglycemia. The long-term adaptation of the beta cell mass to rising glucose concentration is achieved mainly by increasing the number of beta cells through hyperplasia and neogenesis (Bonner-Weir S, 2002; Rhodes C J, 2005).
Type 2 diabetes is also characterized by elevated plasma levels of long-chain FFAs, which further impair beta cell insulin secretion. Normally, FFAs provide essential fuel to the beta cell, but become toxic when chronically present at elevated levels. In the endocrine pancreas, short-term exposure of beta cells to dietary fatty acids potentiates glucose-induced insulin release (Haber E P et al., 2003, Yaney G C and Crokey B E, 2003), while long term exposure impairs insulin secretion and induces secretary failures (lipotoxicity; Lee Y et al., 1994, Unger R H, 2002) and beta cell apoptosis (lipoapoptosis; Shimabukuro M et al., 1998, Lupi R et al., 2002).
There is increasing evidence that lipids can also serve as extracellular ligands for a specific class of receptors and thus act as “nutritional sensors” (Nolan C J et al., 2006). The discovery of these receptors suggested that lipids, specifically, free fatty acids (FFAs), can regulate cell function. Recently, free fatty acids (FFAs) have been demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and have been proposed to play a critical role in physiological glucose homeostasis (Rayasam G V et al., 2007).
GPR40, GPR120, GPR41 and GPR43 exemplify a growing number of GPCRs that have been shown to be activated by free fatty acids (Kotarsky K et al., 2003, Brown A J et al., 2003). GPR40 and GPR120 are activated by medium to long-chain free fatty acids whereas short-chain fatty acids activate GPR41 and GPR43 (Kotarsky K et al., 2003, Nilsson N E et al., 2003, Brown A J et al., 2003).
Each GPR displays a characteristic tissue distribution. GPR40 is preferentially expressed in pancreatic beta cells (Salehi A et al., 2005). The gene encoding GPR40 is located downstream of CD22 on chromosome 19q13.1 (Sawzdargo M et al., 1997) close to a region that has shown linkage to elevated serum triglycerides in families with type 2 diabetes (Elbein S C and Hasstedt S J, 2002). Two polymorphisms, an Arg211His substitution and a rare Asp175Asn mutation have been identified in the GPR40 gene (Haga H et al., 2002). Lately, GPR40 expression was also seen in omental adipose tissue and pancreatic alpha cells (Fodgren E et al., 2007).
It is well established that fatty acids function acutely to maintain basal insulin secretion and to ‘prime’ the islet β-cells to respond to glucose following a prolonged fasting (Gravena C et al., 2002). Furthermore the finding that activation of the receptor resulted in elevation of intracellular Ca2+ via coupling to Gαq/11, leading to activation of PKC suggested a possible role for GPR40 in insulin secretion (Poitout V 2003, Fujiwara K et al., 2005, Schnell S et al., 2007). Down-regulation of GPR40 expression in the mouse insulinoma cell lines resulted in a decrease in the ability of fatty acids to potentiate insulin secretion (Itoh Y et al., 2003, Shapiro H et al., 2005). GPR40 was shown to play a role not only in fatty acid modulation of insulin secretion, but also in GSIS after high-fat feeding (Kebede M et al., 2008).
To investigate the role of GPR40 on metabolism, several groups have studied the phenotype of GPR40 knock out or GPR40 over-expression in different rodent models. GPR40−/− mice on HFD became as obese as their wild type (WT) counterparts but were protected from obesity-induced hyperinsulinemia, glucose-intolerance, hepatic steatosis, hypertriglyceridemia and increased hepatic glucose output (Steneberg P et al., 2005). Another group investigating the effect of chow diet on GPR40−/− mice showed the lack of loss of acute palmitate stimulated GSIS (50% reduction) in isolated islets. On the other hand, these islets did not show any effect on inhibition of GSIS after 72 hr of exposure to palmitate or oleate, compared to WT (Latour M G et al., 2007). In another study, when GPR40 was specifically over-expressed in pancreatic beta cells, the transgenic mice become glucose intolerant, lost first-phase insulin secretion and finally became diabetic. Beta cell morphology was also affected in these mice (Steneberg P et al., 2005).
Though the above mention observations favour antagonism of GPR40 as a control of diabetes, another set of studies proved the opposite. A comprehensive study with a series of potent and selective agonists for GPR40 showed that these compounds significantly enhanced GSIS in wild type but not in GPR40−/− mice. They also showed lowering of blood glucose in streptozotocin-induced diabetic rats and high fat diet induced obese mice. These compounds didn't seem to mediate the chronic toxic effect of free fatty acids on islets (Tan C P et al., 2008). In another recent report, it has been shown that though GPR40 is required for insulin secretion in response to FFA GPR40−/− mice were not protected from high fat diet induced insulin resistance or hepatic steatosis (Lan H et al., 2008).
As fatty acids potentiate insulin secretion in a glucose-sensitive manner it is conceivable that if the effects of fatty acids on insulin secretion are mediated at least in part through GPR40, a small-molecule GPR40 agonist may act as a glucose-sensitive secretagogue (Briscoe C P et al., 2006).
It has recently been shown that GPR40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that GPR40 mediates FFA-stimulated incretin secretion (Edfalk S et al., 2008, Parker H E et al., 2009).
It is well established that acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs beta-cell function and induces apoptosis. It was observed that oleic acid, action of which was mediated at least in part through GPR40, could protect NIT-1 cells from palmitate-induced lipoapoptosis. Moreover, it was found that oleic acid promoted the activation of extracellular signal-regulated protein kinase-MAPK pathway mainly via GPR40, which increased the expression of early growth response gene-1, leading to the anti-lipoapoptotic effect on NIT-1 cells. It was suggested that GPR40 might be implicated in the control of beta-cell mass plasticity (Zhang Y et al., 2007).
Clinical studies have shown that total body fat mass is related to both bone density and fracture risk and that fat ingestion reduces bone turnover. These effects are at least partially mediated by endocrine mechanisms, but it is possible that lipids might act directly on bone. Receptors known to bind fatty acids were found to be expressed in osteoblastic (GPR120) and osteoclastic (GPR40, 41, 43, 120) cells. A synthetic GPR 40/120 agonist mimicked the inhibitory effects of fatty acids on osteoclastogenesis (Cornish J et al., 2008).
GPR40 was recently identified in neurons throughout the brain. Recent studies show that polyunsaturated fatty acids (PUFA) are capable of improving hippocampal long-term potentiation, learning ability of aged rats, and cognitive function of humans with memory deficits. It is probable that certain PUFA may act, as endogenous ligands, on GPR40 on the neuronal cell surface (Yamashima T, 2008).
In another study involving adult monkeys showed that the GPR40 protein increased significantly in the second week after global cerebral ischemia as compared with the control. This data suggest that GPR40 might have a role in regulating adult hippocampal neurogenesis in primates (Ma D et al., 2007; 2008).
Accordingly compounds that modulate GPR40 are expected to have useful therapeutic properties especially in relation to metabolic conditions such as diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulemia, hypercholesteremia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipedemia, metabolic syndrome X, atherosclerosis, diabetic neuropathy, diabetic retinopathy, and hypoglycemia,
Compounds of this type may also be useful in the treatment of cognitive disorders, osteoporosis, inflammatory disorders, cardiovascular disease, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, sexual dysfunction, dermatopathy, dyspepsia, cancer and edema. As such there is significant interest in the development of compounds with this mode of action.